Structure-function studies on the AT1 receptor that mediates most of the known actions of angiotensin II (Ang II) have revealed further aspects of its ligand binding site and the domains involved in receptor activation, signaling, and internalization. The amino acid residues required for binding of the non-peptide antagonist, losartan, are confined to the transmembrane domains of the receptor. In contrast, those involved in binding of peptide antagonists and Ang II itself are known to be located largely within extracellular regions of the receptor. Although the losartan binding site has been proposed to be distinct from that of Ang II, at least three transmembrane residues (Arg169, Lys199, and Phe301) participate in binding of both Ang II and losartan. Thus, peptide ligands such as Ang II interact with the intramembrane binding pocket as well as with extracellular residues that subserve high-affinity binding. Non-peptide antagonists block receptor activation by occupying an intramembrane site that overlaps with the the space occupied by the agonist, or by inducing conformational changes that prevent agonist binding. Agonist-induced internalization of the Ang II receptor was found to depend on a cytoplasmic Ser-Thr-Leu motif that is conserved in the carboxyterminal tail of AT1 receptors but is absent from the non- internalizing AT2 receptor. The conserved Arg-Pro-x-x-Tyr motif located in the seventh transmembrane domain of most G protein-coupled receptors, which is an internalization signal in many growth factor receptors, does not control endocytosis of the AT1 receptor. However, the Phe301 residue contributes significantly to agonist binding and Asn298 is required for normal receptor activation and signal transduction. A tyrosine residue in the fifth transmembrane domain that is highly conserved among G protein-coupled receptors was found to be essential for receptor activation and may be of general importance in signal transduction by seven transmembrane domain receptors. Studies on receptor-mediated signaling responses showed that the potentiation of agonist-induced cAMP production in bovine glomerulosa cells is prevented by inhibitors of the calcium/calmodulin-regulated protein phosphatase, calcineurin. In cultured bovine glomerulosa cells, Ang II stimulated growth responses including activation of MAP kinase and early gene expression, as well as increased thymidine uptake and cell proliferation. The recently discovered ability of the anti-inflammatory agent wortmannin to prevent sustained inositol phosphate and calcium signaling responses to Ang II and other calcium-mobilizing hormones was found to result from inhibition of a novel phosphatidylinositol 4-kinase that is essential for the maintenance of the agonist-sensitive phosphoinositide pools in several cell types.